1. Field of the Invention
This invention relates to a method for the preparation of trans-6-[(2-aryl-substituted cycloalkenyl and substituted cycloalkyl)alkenyl and alkyl]-3,4,5,6-tetrahydro-2H-pyran-2-ones. More particularly, the invention relates to a novel method for the preparation of 2-aryl-1-cyclohexene-1-carboxaldehydes from 1-arylcyclohexenes which are intermediates for trans-6-[(2-arylsubstituted cycloalkenyl and substituted cycloalkyl)alkenyl and alkyl]-3,4,5,6-tetrahydro-2H-pyran-2-ones. The latter compounds, their corresponding ring opened hydroxy acids and pharmaceutically acceptable salts thereof are potent inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (hereinafter HMG-CoA reductase).
2. Reported Developments
Inhibitors of HMG-CoA are effective in lowering blood plasma cholesterol level as well as inhibiting the biosynthesis of cholesterol in humans. As such, inhibitors of HMG-CoA are useful in the prevention and treatment of coronary heart diseases. The prior art recognizes the importance of such compounds, e.g., Bethridge et al., Brit. Med. J., 4,500 (1975) and Brown et al., Scientific American, 58 Nov. (1984). Illustrative references directed to such compounds follow.
U.S. Pat. No. 4,681,893 to B. D. Roth pertains to trans-6-[2-(3-or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-ones useful as hypocholesterolemic agents.
U.S. Pat. No. 4,668,669 to Hoffman et al. discloses semi-synthetic analogs of compactin and mevinolin and the dihydro and tetrahydro analogs thereof for antihypercholesterolemic application.
U.S. Pat. No. 4,282,155 to Smith et al., is directed to 6(R)-[2-(8'-Etherified-hydroxy-2', 6'-dimethylpolyhydronaphthyl-1')ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H- pyran-2-ones for inhibition of biosynthesis of cholesterol.
U.S. Pat. No. 4,567,289 to Willard et al., relates to methyl, ethyl, n-propyl, 2-(acetylamino)ethyl, or 1-(2,3-dihydroxy)propyl ester of E-(3R,5S)-7-(4'-fluoro-3,3',5trimethyl-[1,1'-biphenyl]-2-yl)-3,5-dihydroxy -6heptenoic acid that are HMC-CoA reductase inhibitors.
U.S. Pat. No. 4,611,067 to Volante et al., discloses a process for the preparation of HMG-CoA reductase inhibitors which contain a 4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one moiety.
U.S. Pat. No. 4,900,754 to Regan et al., discloses trans-6-[(2-aryl-substituted cycloalkenyl and substituted cycloalkyl)alkenyl and alkyl]-3,4,5,6-tethydro-2H-pyran-2-ones and methods for their preparation. While the preparative methods are satisfactory to obtain the desired compounds, they are somewhat cumbersome and long. The present invention is directed to a much shorter, more economical method which is especially suited to large-scale manufacturing.